1. Field of the Invention
The present invention relates to a method for preventing and/or treating the clinical illness currently termed systemic inflammatory response syndrome (SIRS) including sepsis (SIRS/sepsis). The present invention also relates to pharmaceutical compositions useful for the prevention and/or treatment of SIRS/sepsis.
2. Discussion of the Background
Inflammation, a component of host protection, is the composite, successive events in response to an injury that may be infectious or non-infectious. Inflammation involves a wide variety of physiologic, cellular and molecular events, including vasodilatation; increased vascular permeability; extravasation of plasma leading to interstitial edema; chemotaxis of neutrophils, macrophages and lymphocytes; activation of complement; and stimulation of antibodies.
Important proximal mediators of this response include two inflammatory cytokines, interleukin-1.beta. (Il-1.beta.) and tumor necrosis factor alpha (TNF.alpha.) (Hamilton G, et al., Scand. J. Infect. Dis., 1992; 24:361; and Bone R C, Crit. Care Med. 1996; 24:163). They are produced primarily by macrophages, assist beneficially in the local inflammatory response, and act in conjunction with other cytokines, prostaglandins, leukotrienes, complement, histamine, serotonin, substance P, and other mediators.
Bacterial infection and other potent stimuli often initiate a marked augmentation of pro-inflammatory cytokines that results in systemic inflammation (Burrell R, Circ. Shock, 1994; 43:137; and Bahrani S, et al., Prog. Clin. Biol. Res., 1995; 392:197). This condition is termed the "systemic inflammatory response syndrome" (SIRS). It may be self-limited or lead to a "multiple organ dysfunction syndrome" (MODS) (e.g., varying degrees of fever, hypoxemia, tachypnea, tachycardia, endothelial inflammation, myocardial insufficiency, hypoperfusion, altered mental status, vascular collapse, which may culminate in end-organ damage such as acute respiratory distress syndrome, coagulopathy, cardiac failure, renal failure, shock, and/or coma) (see: American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference, Crit. Care Med., 1992; 20:864; and Bone R C, JAMA, 1995; 273:155).
When SIRS is caused by infection, it is termed sepsis which, in turn, has progressively severe stages (severe sepsis, and septic shock). The diagnosis of sepsis does not obligate the demonstration of microorganisms, which may be presumed rather than demonstrated. Consequently, some authors subdivide the sepsis syndromes into "culture-positive" indicating that the causative microorganism(s) has(have) been identified, and "culture-negative" implying that the SIRS/sepsis is presumed to be caused by an infectious agent (see: Rangel-Fausto M S, et al., JAMA, 1995; 273:117). SIRS/sepsis is a self-perpetuating condition. Depending on the severity of the condition, the mortality rate averages 20-70%.
In the United States, nearly one-half million cases occur yearly; it has been estimated to represent the 13th leading cause of death, and is the major proximate cause of mortality in intensive care units (Centers for Disease Control, MMWR, 1990; 39:31; and Lowry S F, Crit. Care Med., 1994; 22:S1-2).
Although the serum levels of certain proinflammatory cytokines tend to be higher with SIRS/sepsis, clinical trials have revealed a rather poor correlation between these levels and the degree of organ dysfunction, overall clinical course, or survival (Bone R C, Crit. Care Med. 1996; 24:163). Moreover, some cytokines may exist both in cell-associated and free forms, and only the latter are easily measured. Furthermore, because many cytokines have paracrine or autocrine functions, their levels may be elevated in local pools only and may not be detectable in the systemic circulation. Also, cytokines typically increase only transiently and may not be detected with a single serum sampling. Other rough correlates of sepsis include the acute-phase polypeptide, C-reactive protein, originating from the liver, and neopterin (Grabosch R, et al., Burns, 1992; 18-113), a heterocyclic metabolite produced by macrophages when they are stimulated by endotoxin or interferon-.gamma.. Importantly, to date, there has been no reliable marker for the presence, the course, the response to therapy, or the prognosis of SIRS/sepsis (Bone R C, Crit. Care Med. 1996; 24:163).
It has become apparent that infectious diseases and SIRS/sepsis (with or without known infection) are often characterized by varying degrees of hyperprocalcitonemia; indeed, serum procalcitonin (ProCT) and/or some of its components can reach enormous levels (Becker K L, et al., Anat. Rec., 1993; 236:136; Assicot M, et al., Lancet, 1993; 341:515; Becker K L, et al., "The hyperprocalcitonemia of severe infections," Endocrine Society, Washington, D.C., June 1995; and Becker K L, et al., "Hyperprocalcitonemia as a clinical marker for systemic inflammation," ICAAC, New Orleans, La., Sep. 16, 1996). Increased levels of ProCT and its components have been found in acute pulmonary illnesses, such as bacterial pneumonia or aspiration pneumonitis, that normalized with recovery. Patients with residual disease continued to have levels above normal (Becker K L, et al., The Endocrine Lung in Health and Disease, W B Saunders, Philadelphia, 1984; p. 277; and Nylen E S, et al., Am. J. Med. Sci. 1996; 312:12). Using specific antisera to ProCT, to the amino terminus of ProCT (nProCT), to calcitonin (CT), and to the calcitonin carboxyl peptide-I (CCP-I), in conjunction with HPLC and gel filtration techniques, it has been demonstrated that these patients have markedly increased serum levels of intact ProCT, nProCT, and usually the uncleaved CT:CCP-I peptide. However, mature CT usually remains normal or minimally elevated (Snider, R et al., "Characterization of the hyperprocalcitonemia of inflammatory/infectious disorders," Am. Fed. Clin. Res., New Orleans, La., Feb. 1, 1996; Becker, K L, et al., "The hyperprocalcitonemia of severe infections: Associated secretion of other constituents of the prohormone," Endocrine Society, Washington, D.C., Jun. 14-17, 1995).
Subsequently, in other infections (staphylococcus-induced toxic shock syndrome (Sperber S J, et al., Rev. Inf. Dis., 1990; 12:736), bacterial meningitis (Assicot M, et al., Lancet, 1993; 341:515), melioidosis (Smith M D, et al., Clin. Infect. Dis., 1995; 20:641), acute falciparium malaria (Davis T M E, et al., Trans. Roy. Soc. Trop. Med. Hyg., 1994; 88:670), pyelonephritis (Becker K L, et al., "The hyperprocalcitonemia of severe infections," Endocrine Society, Washington, D.C., Jun. 14-17, 1995), etc.), serum ProCT levels as high as 200 ng/mL were reported. The SIRS which is secondary to pancreatitis (Becker K L, et al., Endocrine Society, Washington, D.C., June 1995; and White J., et al, Pancreas Club, San Francisco, Calif. May 19, 1996), burns (O'Neill W., et al, J. Burn Care Rehab., 1992; 13:605; and Becker K., et al. Anat. Rec., 1993; 236:136), and heat stroke (Nylen E S, et al., Crit. Care Med. (In Press), 1997), also were found to manifest high serum levels of CT precursors (i.e., ProCT and/or its components).
In severe burns, greatly elevated levels of ProCT and/or its components were found, which correlated positively with mortality; these levels had considerable prognostic utility, sufficient to influence the type and aggressivity of therapy (Nylen E, et al., Horm. Metab. Res., 1992; 24:439; and Nylen E S, et al., Respir. Med., 1995; 89:41). It has since been determined that the high levels of CT precursor forms found in these patients consist mostly of ProCT, nProCT and the CT:CCP-I peptide, with mature CT being either normal or minimally elevated.
Interestingly, a linkage between endotoxin, inflammatory cytokines, and hyperprocalcitonemia was demonstrated by an experiment in which injection of endotoxin from E. coli bacteria into volunteers produced fever, chills and myalgia; serum TNF.alpha. increased to peak serum levels at 11/2 hr, and Il-6 peaked at 6 hr (Dandona P, et al., J. Cin. Endocrinol. Metab., 1994; 79:1605). Both of these cytokines then gradually normalized. Serum ProCT, initially undetectable, peaked at 6 hours (4.5 ng/mL), and thereafter maintained a plateau until at least 24 hr. Mature CT remained undetectable.
The conventional treatment of SIRS/sepsis varies according to the initiating cause (e.g., burns, infection, multitrauma, pancreatitis). Therapy may include cardiovascular support such as fluids and adrenergic agents, antibiotics, corticosteroids, respiratory assistance, oxygen, renal dialysis, etc. In addition, antibodies or antagonists to cytokines or endotoxin have been evaluated (Zeigler, E J, et al, New. Engl. J. Med., 1991; 324:429; and Christman, J W, et al., Crit. Care Med., 1995; 25:955). However, in spite of these therapies, SIRS and the sepsis syndromes continue to have an extremely high morbidity and mortality (Natanson, C, et al., Ann Int Med, 1994; 120:771; Suffredini, A F, Crit. Care Med., 1994; 22:512; and Fisher, C J, et al, New Eng. J. Med., 1996; 334:1697). Thus, there is no very effective method for preventing and/or treating SIRS, and there remains a very compelling need for alternative methods for preventing and/or treating SIRS/sepsis. There also remains a need for pharmaceutical compositions useful for preventing and/or treating SIRS/sepsis.